Hematological cancers are cancers originating in blood-forming tissue, such as bone marrow, or in the cells of the immune system. Hematological cancers include leukemia, lymphoma, and multiple myeloma and they account for nearly 10% of newly diagnosed cancer in the United States.
One type of hematological cancer, acute myeloid leukemia (AML), is a hematological cancer characterized by abnormal proliferation of myeloid progenitor cells having lost the ability to differentiate. According to statistics collected by the American Cancer Society, the estimated incidence of AML in the United States is nearly 15,000 new cases in 2013 with an estimated mortality of at least 10,000 for that same year. The standard of care for AML has changed little over the decades, comprising the administration of various combinations of cytotoxic chemotherapy drugs (commonly the two-drug regimen of cytarabine and daunorubicin), with the goal of eliminating leukemic blasts while restoring normal blood counts. According to the National Cancer Institute, standard chemotherapy results in about 65% complete response rate, with more than 25% of adults expected to survive three of more years. However, given the high rate of relapse and low tolerance to chemotherapy in older patients, researchers have been investigating targeted therapies that specifically inhibit protein targets that have been identified as mediators of leukemic blast cell survival.
One such identified protein target is the FMS-like tyrosine kinase III, or FLT3, which is a kinase protein belonging to the class III receptor tyrosine kinase family, which also includes the receptors, PDGFRα, PDGFRβ, KIT, RET, and CSF1R. FLT3 is a receptor tyrosine kinase that plays a role in the regulation of normal hematopoiesis and which is overexpressed in leukemic blast cells (See Heinrich Mini Reviews in Medicinal Chemistry 2004 4(3):255-271, Kiyoi et al. Int J Hematol 2005 82:85-92). About 30% of all AML patients are also found to have an activating mutation in the FLT3 gene in the form of internal tandem duplications called FLT3-ITD which is associated with poor prognosis and higher rate of relapse. FLT3 inhibitors that have been studied or are currently being studied in the clinic include PKC412 (midostaurin), CEP701 (lestarutinib), SU-5416 (semaxinib) and AC220 (quizartinib). More recently, acquired drug resistance mutations conferring resistance against FLT3 inhibitors have been identified in patients who received FLT3-targeted therapy (See Smith et al. Nature 2012 485(7397):260-263 and von Bubnoff et al. Cancer Res. 2009 69(7):3032-3041).
There remains a need to provide novel classes of compounds that are useful in the treatment of FLT3-mediated diseases or disorders, including those that have acquired resistance to FLT3-targeted therapy. Such classes of compounds would also be useful in the treatment of inflammatory and autoimmune disorders as FLT3 is expressed in a large portion of dendritic cell progenitors and plays a role in the proliferation and differentiation of these progenitors into dendritic cells which are the main initiators of T-cell mediated immune response.